Dihydroxylphenyl amides as inhibitors of the Hsp90 molecular chaperone.
Information from X-ray crystal structures were used to optimize the potency of a HTS hit in a Hsp90 competitive binding assay. A class of novel and potent small molecule Hsp90 inhibitors were thereby identified. Enantio-pure compounds 31 and 33 were potent in PGA-based competitive binding assay and inhibited proliferation of various human cancer cell lines in vitro, with IC(50) values averaging 20 nM.
Kung
Pei-Pei
PP
Pfizer Global Research and Development, La Jolla Laboratories, 10770, Science Center Dr., San Diego, CA 92121, USA. peipei.kung@pfizer.com
Funk
Lee
L
Meng
Jerry
J
Collins
Michael
M
Zhou
Joe Zhongxiang
JZ
Johnson
M Catherine
MC
Ekker
Anne
A
Wang
Jeff
J
Mehta
Pramod
P
Yin
Min-Jean
MJ
Rodgers
Caroline
C
Davies
Jay F
JF
Bayman
Eileen
E
Smeal
Tod
T
Maegley
Karen A
KA
Gehring
Michael R
MR
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000596:Amino Acids / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000577:Amides; D000596:Amino Acids; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones